One major reason for the devastating and permanent disabilities after spinal cord and other types of CNS injuries is the inability of lesioned axons to regenerate and re-build the functional circuits. Thus, a long- standing challenge has been to find ways to promote axon regeneration and restore functions. Among different types of descending axons, corticospinal tract (CST) axons appear to be the most refractory to regenerate. Because of its critical role in controlling voluntary movement, developing a strategy to promote CST regeneration will be paramount for functional recovery after spinal cord injury. Despite considerable efforts over the past decades from both basic and clinical sides, currently there is no method that enables regeneration of CST axons even in experimental spinal cord injury models in mammals. In our recent studies towards understanding the intrinsic regenerative ability of CNS neurons, we discovered that conditional deletion of PTEN, a negative regulator of the mTOR activity, leads to robust axon regeneration after optic nerve injury in the adult mice (1). Strikingly, our further studies demonstrated similarly robust regeneration of CST axons in two different spinal cord injury models, namely T8 dorsal hemisection and T8 spinal cord complete crush (See Preliminary Studies). These exciting results of anatomical regeneration provide an unprecedented opportunity to assess whether these regenerating axons are able to form functional connection and mediate functional recovery after spinal cord injury, which is the objective of this proposed study. PUBLIC HEALTH RELEVANCE: Most of functional deficits and disabilities after spinal cord injury are due to the disruption of the longitudinal projecting axonal tracts that interconnect brain and spinal cord. Thus, developing therapies to restore sensory motor control of upper body is of very high priority. This line of research was initiated to test a simple yet novel hypothesis that the mechanisms preventing cells from over-growth also play a role in suppressing the intrinsic axon regenerative ability of adult neurons. The rationale was based on the similarities between development- dependent declines of neuronal axon growth abilities and the ceased growth in size of any mature differentiated cells. By examining axon regeneration in different RGC specific gene deletion mice, we discovered that deleting PTEN or TSC1 allows consistent and remarkable optic nerve regeneration after injury (1). Our further studies demonstrated robust CST regeneration in two different types of spinal cord injury models. Thus, the experiments proposed in this proposal will be designed to assess the functional outcomes, which are expected to provide important insights into designing therapeutic strategies for spinal cord injury.